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Article
Nature Structural & Molecular Biology  11, 308 - 315 (2004)
Published online: 7 March 2004; | doi:10.1038/nsmb740

Regulation of the p300 HAT domain via a novel activation loop

Paul R Thompson1, 8, Dongxia Wang1, Ling Wang1, Marcella Fulco2, Natalia Pediconi3, Dianzheng Zhang4, Woojin An5, Qingyuan Ge6, Robert G Roeder5, Jiemin Wong4, Massimo Levrero3, 7, Vittorio Sartorelli2, Robert J Cotter1 & Philip A Cole1

1  Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

2  Muscle Gene Expression Group, Laboratory of Muscle Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program, National Institutes of Health, 50 South Drive, Room 1146, Bethesda, Maryland 20892-8024, USA.

3  Laboratory of Gene Expression, Fondazione Andrea Cesalpino, University of Rome La Sapienza, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy.

4  Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

5  Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10021, USA.

6  Cell Signaling Technology, Beverly, Massachusetts 01915, USA.

7  Department of Molecular Oncogenesis, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy.

8  Current address: Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA.

Correspondence should be addressed to Philip A Cole pcole@jhmi.edu
The transcriptional coactivator p300 is a histone acetyltransferase (HAT) whose function is critical for regulating gene expression in mammalian cells. However, the molecular events that regulate p300 HAT activity are poorly understood. We evaluated autoacetylation of the p300 HAT protein domain to determine its function. Using expressed protein ligation, the p300 HAT protein domain was generated in hypoacetylated form and found to have reduced catalytic activity. This basal catalytic rate was stimulated by autoacetylation of several key lysine sites within an apparent activation loop motif. This post-translational modification and catalytic regulation of p300 HAT activity is conceptually analogous to the activation of most protein kinases by autophosphorylation. We therefore propose that this autoregulatory loop could influence the impact of p300 on a wide variety of signaling and transcriptional events.

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Nature Structural & Molecular Biology
ISSN: 1545-9993
EISSN: 1545-9985
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